I. Technical Field
The present invention relates generally to the fields of microbiology and bacterial genetics. More particularly, it concerns the cloning of the biosynthetic pathway for platensimycin from Streptomyces platensis and uses thereof.
II. Related Art
Antibiotic resistance—the ability of a micro-organism to withstand the effects of an antibiotic—is a growing problem in the medical field. Antibiotic resistance evolves naturally via natural selection through random mutation. Because antibiotic action is an environmental pressure, those bacteria that have mutations allowing them to survive will live on to reproduce and pass the trait to their offspring, resulting in a fully-resistant generation. Studies have demonstrated that patterns of antibiotic usage greatly affect the number of resistant organisms that develop, including overuse of broad-spectrum antibiotics (e.g., second- and third-generation cephalosporins), and greatly hastens the development of methicillin resistance, even in organisms that have never been exposed to the selective pressure of methicillin per se. Other factors contributing to resistance include incorrect diagnosis, unnecessary prescriptions, improper use of antibiotics by patients, and use of antibiotics as livestock food additives for growth promotion.
Staphylococcus aureus is one of the major resistant pathogens. Found on the mucous membranes and the skin of around a third of the population, it is extremely adaptable to antibiotic pressure. It was the first bacterium in which penicillin resistance was found—in 1947, just four years after the drug started being mass-produced. Methicillin was then the antibiotic of choice, but has since been replaced by oxacillin due to significant kidney toxicity. MRSA (methicillin-resistant Staphylococcus aureus) was first detected in Britain in 1961 and is now quite common in hospitals. MRSA was responsible for 37% of fatal cases of blood poisoning in the UK in 1999, up from 4% in 1991. Half of all S. aureus infections in the U.S. are resistant to penicillin, methicillin, tetracycline and erythromycin.
This left vancomycin as the only effective agent available. However, VRSA (vancomycin-resistant Staphylococcus aureus) was first identified in Japan in 1996, and has since been found in hospitals in England, France and the U.S. VRSA is also termed GISA (glycopeptide intermediate Staphylococcus aureus) or VISA (vancomycin-insensitive Staphylococcus aureus), indicating resistance to all glycopeptide antibiotics. A new class of antibiotics, oxazolidinones, became available in the 1990s, and the first commercially available oxazolidinone, linezolid, is comparable to vancomycin in effectiveness against MRSA. Linezolid-resistance in Staphylococcus aureus was reported in 2003. Community associated (CA)-MRSA has now emerged as an epidemic that is responsible for rapidly progressive, fatal diseases including necrotizing pneumonia, severe sepsis and necrotizing fascitis.
Enterococcus faecium is another superbug found in hospitals. Penicillin-Resistant enterococcus was seen in 1983, vancomycin-resistant Enterococcus (VRE) in 1987, and linezolid-resistant Enterococcus (LRE) in the late 1990s. Streptococcus pyogenes (Group A Streptococcus) infections can usually be treated with many different antibiotics. Strains of S. pyogenes resistant to macrolide antibiotics have emerged, but all strains remain uniformly sensitive to penicillin. Resistance of Streptococcus pneumoniae to penicillin and other β-lactams is increasing worldwide. The major mechanism of resistance involves the introduction of mutations in genes encoding penicillin-binding proteins. By 1993, Escherichia coli was resistant to five fluoroquinolone variants. Mycobacterium tuberculosis is commonly resistant to isoniazid and rifampin, and sometimes universally resistant to the common treatments. Other pathogens showing resistance include Salmonella, Campylobacter, Streptococci, and Acinetobacter baumannii. 
Clearly then, there remains a need for new antibiotics. Moreover, once new antibiotics are found, there is an equivalent need for methods to produce the antibiotics in sufficient quantities, and a reasonably low cost.